Abstract The majority of schizophrenia patients fail to achieve premorbid status and functional outcomes (e.g. employment, interpersonal relationships, independent living) are very poor, despite effective psychosis symptom reduction with antipsychotic medications. Cognitive impairments are broad and persistent and underlie the functional deficits of the illness. To date, however, there have been no characteristics identified in schizophrenia that provide good predictors for treatment targets of cognitive and functional deficits. Glutamate dysfunction may significantly contribute to the cognitive and functional deficits in schizophrenia. The proposed research is centered around the pathophysiological model of N-methyl-D-aspartate receptor (NMDAR) hypofunction of schizophrenia. This dysfunction produces damage to the dendritic portion of neurons, which leads to chronic cognitive and functional disabilities. Patients who have lower glutamate levels may manifest with broad cognitive impairment and greater social disabilities. Our short-term goal is to characterize the relationship between glutamate, cognition, and functional outcomes in schizophrenia. The documentation of these relationships is essential for us to achieve our long-term goal: to create a model that will allow the selection of specific patients that will be good candidates for glutamatergic modulation drug treatments. The proposed project will use a novel method, proton echo planar spectroscopic imaging (PEPSI) at 3 Tesla, to study glutamate concentrations in distinct cortical gray and white matter regions in schizophrenia. We will also measure N-acetylaspartate compounds (NAAc, a marker of neuronal viability), myoinositol (Ins, a glial marker) and GABA (the major inhibitory neurotransmitter). PEPSI is advantageous over other spectroscopy techniques because it provides superior spatial resolution (1cc voxels), with greater brain coverage (over 130 voxels), and very fast acquisition (under 10 min). To examine neurometabolism across different stages of the illness, 200 subjects with schizophrenia will be equally recruited into two groups: short illness duration (d10 yrs) and long duration (>10 yrs). Symptoms, side-effects, cognitive and social function will be assessed. A group of 200 healthy volunteers, matched in age, gender and parental socioeconomic status to the schizophrenia groups, will also be studied. This project will address four specific pressing issues: 1) The in-vivo examination of the relationship between glutamate, cognition, negative symptoms and social function in schizophrenia. 2) The evaluation of cortical pathology suggestive of dendritic damage (reduced gray matter NAAc), early in the illness. 3) The examination of a compensatory glial up-regulation (increased Ins) in older schizophrenia subjects. 4) The assessment of GABAergic dysfunction in schizophrenia. Documentation that reduced glutamate is a robust correlate of cognition in schizophrenia would support the use of glutamate enhancing agents to optimize cognitive function in vulnerable patients. As 3 Tesla scanners become widely available for standard of care, spectroscopy with PEPSI, may contribute to the identification of such individuals. This application presents extensive pilot data addressing all four of these issues.